JPH0772143B2 - Novel pharmaceutical formulation capable of limiting the rate of movement in the digestive tract - Google Patents

Abstract

Drug carrier capable of controlling the gastrointestinal transit rate of the pharmaceutical preparation, which comprises aqueous polymer and oil, pharmaceutical preparation comprising the same and use thereof for controlling the gastrointestinal transit rate of the pharmaceutical preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pharmaceutical preparation capable of controlling gastrointestinal migration rate. More specifically, the present invention relates to a novel pharmaceutical preparation capable of controlling the gastrointestinal tract migration rate, which is formed by mixing polyethylene oxide or hydroxypropylmethyl cellulose, a medium-chain triglyceride and a drug.

The usefulness of a sustained-release preparation that maintains the blood concentration of a drug at a desired level for a long time has already been recognized.As such a sustained-release preparation, an active ingredient is contained in an insoluble matrix such as paraffin wax and a polymer resin. The sustained-release matrix type tablets which are dispersed and embedded and the sustained-release granules in which the active ingredient is coated with a polymer film for controlling the diffusion of the active ingredient are well known in the pharmaceutical technical field.

However, when the above-mentioned pharmaceutical preparation is used, absorption of the drug from the pharmaceutical preparation into the bloodstream is often unsatisfactory.

In particular, when this kind of pharmaceutical preparation is applied to a drug having a relatively short absorption site in the gastrointestinal tract, insufficient absorption occurs considerably.

The main cause of such inadequate absorption is the relatively fast passage rate of commonly used sustained release formulations at the drug absorption site. (Hereinafter, these commonly used sustained-release preparations that cannot control passage through the digestive tract are called old dosage forms).

Recently, a method for evaluating the gastrointestinal migration rate of various dosage forms, that is, a γ-scintigraphy method has been widely used.

SS Davis, etc. [Int.J.Pharmaceutics, 21 , 16
7-177 (1984)] has obtained data on gastric-duodenal transit time and intestinal transit time of matrix-type tablets and granules, respectively.

The gastro-duodenal and intestinal transit times of the matrix tablet are 164 minutes (SE92 minutes) and 188 minutes (SE23 minutes), respectively. In the case of granules, the former has a half-life of 79 minutes (SE20 minutes) and the latter has a half-life of 227 minutes (SE82 minutes).

If the site of drug absorption is between the duodenum and ileum, a sustained release formulation must be designed to release 100% of the drug in about 360 minutes.

Otherwise adequate absorption would not occur.

In order to overcome the poor absorption of the old dosage form, several researchers have attempted to retain it in the stomach for extended periods of time.

For example, Prabhakar R.shet
h) et al. describe a dosage form floating in the stomach in US Pat. No. 4,167,558.

Such a suspension system attempts to suspend the dosage form in the stomach by making the specific gravity of the dosage form smaller than that of gastric juice.

Therefore, such floating systems are sensitive to the abundance of gastric juice.

Unfortunately, water administered on an empty stomach is known to pass through the gastric pylorus relatively quickly. That is, A. Hurwitz (Hu
rwitz) [Gastroenterology, 71 , 268-273 (1976)] has a half-life of 13.1 min (SE0.7
Minutes).

Furthermore, during fasting, fasting anal-side-propagating strong contraction movement (IM
C) occurs in a cycle of about 100 minutes.

This IMC appears to push the floating system from the stomach into the duodenum. Therefore, the reliability of this floating system is poor.

The inventors of the present invention invented a formulation prepared by mixing polyethylene oxide or hydroxypropylmethylcellulose, a medium-chain triglyceride and a drug, and being able to control the gastrointestinal migration rate and drug release of the pharmaceutical formulation, which is a drawback of the old dosage form. Was able to overcome.

The present invention will be described in more detail below.

The weight ratio of polyethylene oxide or hydroxypropyl methylcellulose and the medium-chain triglyceride is selected depending on the degree of controlling the movement of the pharmaceutical preparation in the digestive tract,
A preferred weight ratio is 2: 1 to 1:40 (more preferably 3: 2 to 1: 1).
30, most preferably 1: 1 to 1:20).

The weight ratio of the drug used in the pharmaceutical preparation to polyethylene oxide or hydroxypropylmethyl cellulose, which is a drug carrier, and medium-chain triglyceride is selected depending on the kind of the drug, the degree of controlling the migration in the digestive tract of the pharmaceutical preparation, and the like. And the drug weight ratio is 3: 2 to 1: 400 (more preferably 1: 1 to 1: 300, most preferably 1: 3 to 1:20).
0).

The present invention will be described according to the following examples.

[Drugs in Examples] (1) 7- [2- (2-aminothiazol-4-yl)
-2-Carboxymethoxyiminoacetamide] -3-
Vinyl-3-cephem-4-carboxylic acid (syn isomer)
(Hereinafter referred to as FK027).

(2) Cephalexin (hereinafter referred to as CEX) (3) Isopropyl 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (hereinafter referred to as FK235 (4) 3,4-dihydro-6- (3,4-dimethoxyphenyl) -1-ethyl-3-methyl-4- (2,4,6-trimethylphenylimino) -2 (1H) -pyrimidinone (Hereinafter, referred to as FR58664) Example 1 A capsule of Table (1) was prepared by using poly (ethylene oxide) [average molecular weight 5,000,000: manufactured by Aldrich Chemical Co., Ltd .:
PIG], Miglyol 812 [Trademark: Dynamit Novell Chemicals: M812] and
Obtained by mixing FK027 and filling capsules.

Example 2 A capsule of Table (2) was prepared by using hydroxypropylmethylcellulose 2208 (15000 cps) [Japanese Pharmacopoeia 10th edition; hereinafter HPMC
, M812 and FK027 are mixed and filled into capsules.

Example 3 CEX (160 mg) was added to 5% (w / v) hydroxypropylmethylcellulose 2910 (6 cps) (JP 10th edition), that is, TC-5R.
[Trademark: manufactured by Shin-Etsu Chemical] Suspended in an aqueous solution (700 ml), and this suspension is "non-pareil" (350-500 μm) (80 g)
[Trademark: Made by Freund] "Flow Coater Mini"
CEX-containing particles are obtained by spraying using [trademark: manufactured by Freund].

The average particle size and CEX content of the obtained particles are 650μ, respectively.
m and 55.54% (w / w).

In the next step, the particles obtained above were treated with hydroxypropylmethylcellulose phthalate “HP-50” (17.85 g) [trademark: manufactured by Shin-Etsu Chemical], cetyl alcohol (3.15 g), ethanol (110 ml) and methylene chloride (110 ml). A CEX-containing enteric coated particle is obtained by coating with a solution for enteric film using "Flow Coater Mini".
called ep).

The average particle size and CEX content of CEXep are 750 μm and 43.22% (w / w), respectively.

The capsules of Table (3) are obtained by mixing CEXep, PEO and M812 and filling the capsules.

The test results are described below to show the usefulness of the pharmaceutical preparation of the present invention.

I. Test (I): Passing Test Test Samples Test samples A-C in Table (4) were made by mixing FK027, PEO, M812 and indigo carmine (hereinafter referred to as IC) to produce 1/8 ounce capsules. (Chemical and Pharmaceuticals) is used.

Test Method Each test sample is orally administered with water (40 ml) to an overnight fasted male Beagle dog (8-12 kg) and the animals are housed in cages.

Pentobarbital sodium (30 mg / kg) is intravenously injected at 3, 6 or 9 hours after administration for anesthesia, and the inside of the stomach of each animal is observed with an endoscope in the left prone position.

This test is performed 5 times for each test sample.

In addition, as a control experiment, the same test was performed on non-disintegrating matrix tablets (10 mmφ × 5 mm) instead of the test sample.
Do it once.

result O: The test sample (or tablet) remained in the stomach.

X: The test sample (or tablet) did not remain in the stomach.

−: Experiment not conducted From the test results, the gastro-duodenal migration time of test samples A to C is longer than that of the non-disintegrating matrix tablet, and the gastric-duodenal migration time of the pharmaceutical preparation depends on the PEO concentration in the carrier. You can see that

As a result of endoscopic observation, it was found that the pharmaceutical preparation containing the drug carrier of the present invention spreads and adheres to the inner surface of the stomach.

II. Test (II): Drug Release Test Test Samples Test samples D to H in Tables (6) and (7) were tested using FK02.
Manufactured by mixing 7, PEO (or HPMC) and M812.

Method Japanese Pharmacopoeia 10th edition 2nd method (paddle method, 100 rpm, artificial gastric juice)
Dissolution test according to 900ml, 37 ℃.

The test sample is placed in a 10 drop dissolution test container from a plastic syringe.

Results The dissolution behavior of the test sample is shown in Table (8) below.

As a result, it can be seen that the rate of drug release slows as the amount of water-soluble polymer in the drug carrier increases.

III. Test (III): Serum Concentration Test- (1) (i) Production of New Dosage Form (NDF) Type 1 Test Samples Test samples I to O in Tables (9) and (10)
Manufactured by mixing 7, PEO (or HPMC) and M812.

1/8 each of sample and 1 ml of M812 and 0.4 ml of M812
Fill into ounce and 1/70 ounce capsules.

In the future, this type of new dosage form (NDF), in which the drug is contained in the drug carrier as a simple untreated powder, will be designated as NDF type 1
Called.

Three different release rate tablets (containing 125 mg titre of FK027) are manufactured according to conventional methods as representative of the old dosage form (ODF).

The dissolution rate of FK027 from ODF is the method described in the Japanese Pharmacopoeia 10th edition (paddle method, 100 rpm, artificial gastric juice 900 ml, 37 ° C).
To measure.

The data obtained are shown in Table (11) below.

(Iii) Measurement of serum FK027 concentration: 6 beagle dogs (male, 8
-12kg) orally. FK027 solution in phosphate buffer 2
0 ml (250 mg titer or 125 mg titer) is administered to beagle dogs in each group as a control.

Immediately after the administration of each sample, 40 ml of water (20 ml in the case of the control FK027 aqueous solution) is administered.

The serum concentration of FK027 is measured by high performance liquid chromatography (HPLC method).

(Iv) Results The results of serum FK027 concentration of NDF and ODF are shown in Table (1).
2) and (13).

Comparing the results of NDF and ODF shows that NDF
It can be seen that, especially when a large amount of water-soluble polymer is used, a high serum concentration is maintained for a long time, that is, the maximum concentration is obtained in 10 hours.

On the other hand, three types of ODF show a decrease in serum concentration after 6 hours.

From these results, the advantage of NDF as compared to ODF is clear, because NDF stays in the stomach for a longer time than ODF.

The known Wagner-Nelson formula (J. Wagner and E. Nelson, J. Pharm. Sci., 52 , 610 (1963)) was used to evaluate the drug absorption from each dosage form into the bloodstream. To do.

The cumulative amount in the bloodstream of each sample is shown in Table (14). From this result, it is clear that the absorption rate from NDF into the bloodstream can be controlled by the amount of the water-soluble polymer suspended in the drug carrier.

The absorption controllability of this NDF is based on the controllability of drug release from the drug carrier as described in Test (II) (drug release test).

The absorption time from N.D.F. is calculated to be about 10 hours or more.

On the other hand, the values obtained by ODF show that the absorption time for all three types is limited to about 6 hours. The reason for the limited absorption time of ODF is that the drug release from ODF is still sustained, but ODF passes through the absorption site relatively quickly.

IV: Test (IV): Serum concentration test- (2) Effect of food on serum concentrations of NDF and ODF NDF test sample Test sample K described in Test III is used as a representative of NDF.

ODF test sample Use the test sample ODF (FK027) (3) described in Test III.
Used as a representative of ODF.

Method Diet (100 g) is given to 3 dogs 30 minutes before test sample administration. Immediately after the administration of each sample, water (40 ml) is administered.

Results The test results are shown in Table (15).

ODF results show fasting FK02 6 hours after administration
7 There is a significant difference between serum and postprandial serum levels,
AUC is also declining.

This significant difference in serum concentration and AUC between fasting and postprandial seems to be based on the difference between the fasting and postprandial total gastrointestinal transit time of ODF.

In the case of NDF, the difference in serum concentration between fasting and postprandial was small overall, and AUC was almost the same.

From these results, it can be said that NDF produced using the drug carrier of the present invention is less affected by diet than ODF.

V: Test (V): Serum concentration test- (3) (i) NDF type 2 If the gastric juice solubility of the test drug is relatively high, the drug release from the NDF type 1 is such that the drug carrier remains in the stomach. Will end up much faster than time. Therefore, in this case, it seems that NDF type 1 cannot sufficiently exert the advantages of the drug carrier.

The following NDF type 2 can be used in such a case. Describe NDF type 2 using CEX as the applicable drug.

Test Sample P Capsules (8) in Table (3) were used as Test Sample P (1/8 ounce capsules used) (ii) ODF of CEX To compare NDF type 2 and ODF, two different release rates were used. The tablets shown are manufactured as ODF of CEX. C
The ODF of EX is manufactured by a usual method.

The release rate of CEX from the obtained O.D.F. is shown in Table (16).

The dissolution test method is the same as test (III).

(Iii) Measurement of serum concentration of CEX These samples [Sample P, ODF (CEX) (1)
And ODF (CEX) (2)] are each administered to 6 identical beagle dogs fasted overnight.

The CEX concentration in serum is measured by the HPLC method. The results are in table (1
Shown in 7).

The results for sample P show that CEX is absorbed into the bloodstream for a long time.

However, the two types of ODF of CEX are C in serum after 4 hours.
It shows a decrease in EX concentration and a decrease in AUC.

According to Wagner-Nelson analysis (Table (18)), sample P, ODF (CEX) (1) and ODF (CEX) (2)
The CEX absorption times are 10 hours or more, about 6 hours and about 6 hours, respectively.

From the above results, it can be seen that NDF type 2 is superior in formulation to ODF.

Of course, NDF type 2 is not limited to the above dosage form.

It can be applied not only to enteric film-coated drug particles but also to film (eg, ethyl cellulose) -coated sustained-release particles.

Example 4 FK235 (8.5 g) and TC-5R (25.5 g) are dissolved in a 1: 1 mixture of ethanol and methylene chloride (850 ml).

Low-substituted hydroxypropyl cellulose "L-HP
C _LH31 "[trademark: manufactured by Shin-Etsu Chemical] (42.5 g) is added to the above solution and suspended. This suspension was sprayed onto "Nonpareil" (350-500μm) (51.4g) using "Flow Coater Mini" to obtain particles, which were sieved to obtain 24 mesh (71
Particles passing through 0 μm) are obtained.

Furthermore, L-HPC in a 1: 1 mixture (800 ml) of ethanol and methylene chloride in which FK235 (8 g) and TC-5R (24 g) were dissolved.
_{An LH31} (40 g) suspension was _{prepared in the same} manner as described above and
Spray on g) to obtain particles containing a solid dispersion of FK235. The average particle size and FK235 content of the obtained particles are 700 μm and 8.6% (w / w), respectively.

In the next step, the FK235 solid dispersion-containing particles obtained above (70 g)
Using the "Flow Coater Mini", "HP-50" (14.4
g), cetyl alcohol (1.6g), ethanol (160ml)
And an enteric film solution consisting of methylene chloride (160 ml). (Hereinafter, referred to as FK235ep).

The average particle size and FK235 content of FK235ep are 750μ
m and 7.2% (w / w).

The capsules in Table (19) are obtained by mixing FK235ep, PEO and M812 and filling the capsules.

VI: Test (VI): Serum concentration test- (4) Test sample (i) NDF of FK235 To clarify the application of our drug carrier to poorly soluble drugs, FK235 with water solubility of 2 μg / ml or less. NDF type 2 is manufactured and tested.

Use capsule (9) in Table (19) as test sample Q (using 1/8 ounce capsules).

(Ii) ODF of FK235 FK235 solid dispersion plain tablet (FK235, 4 mg manufactured by a conventional method
Titer), and FK235ep 111.1 mg containing capsule (FK235,
8 mg titer) was used as the ODF and is hereinafter referred to as control (1) and control (2), respectively.

Measurement of FK235 concentration in plasma Each test sample containing 8 mg titer of FK235 is orally administered to 6 identical beagle dogs (male, 8-12 kg) fasted overnight.

Immediately after the administration of each sample, water (40 ml) is administered.

The FCD235 concentration in plasma is measured by ECD gas chromatography.

The results are shown in Table (20).

The results of sample Q show that FK235 is absorbed into the bloodstream for a long time.

On the other hand, the controls (1) and (2) show FK in plasma after 2 hours.
235 shows a decrease in concentration.

Formulations of another sparingly soluble drug, FR58664, are prepared and studied according to the same method as Sample Q in Test VI.

Similar results are obtained with FR58664 N.D.F.

These results indicate that our drug carrier can also be applied to poorly soluble drugs such as FK235 and FR58664.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-59-62521 (JP, A) JP-A-58-57315 (JP, A) JP-B-45-39839 (JP, B1)

Claims (1)

[Claims] 1. A novel pharmaceutical preparation comprising a mixture of polyethylene oxide or hydroxypropylmethyl cellulose, a medium-chain triglyceride and a drug, which can control the gastrointestinal tract migration rate.